Biologically potent L-hexoses and 6-deoxy-L-hexoses: Their syntheses and applications

Article abstract of DOI:10.1002/jccs.200400175

This account describes our recent work in the development of new methodologies to prepare rare and biologically potent L-hexoses and 6-deoxy-L-hexoses, from cheapest D-glucose, via L-hexofuranoses and 1,6-anhydro-β-L-hexopyranoses as key building blocks. Their applications in the syntheses of heparin oligosaccharides, the carbohydrate moiety of bleomycin A₂, and L-acovenose are also summarized here.

Full text of DOI:10.1002/jccs.200400175

Journal of the Chinese Chemical Society, 2004, 51, 1193-1200
1193
Biologically Potent L-Hexoses and 6-Deoxy-L-Hexoses: Their Syntheses
and Applications
Suvarn S. Kulkarnia (
), Fa-Chen Chib (
) and Shang-Cheng Hunga* (
)
aInstitute of Chemistry, Academia Sinica, Taipei 115, Taiwan, R.O.C.
bDepartment of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan, R.O.C.
This account describes our recent work in the development of new methodologies to prepare rare and bio-
logically potent L-hexoses and 6-deoxy-L-hexoses, from cheapest D-glucose, via L-hexofuranoses and
1,6-anhydro-b-L-hexopyranoses as key building blocks. Their applications in the syntheses of heparin oligo-
saccharides, the carbohydrate moiety of bleomycin A2, and L-acovenose are also summarized here.
Keywords: L-Hexose; 1,6-Anhydro-b-L-hexopyranoses; Bleomycin A2; Heparin.
INTRODUCTION
L-Hexoses and 6-deoxy-L-hexoses (Fig. 1), which are
nificant antitumor drug exhibiting strong activity through
DNA binding and metal-dependent oxidative cleavage of nu-
cleotides in the presence of oxygen. It belongs to a family of
glycopeptide antibiotics and contains a disaccharide moiety
consisting of a a1®2 linked 3-O-carbamoyl-D-mannopyr-
anose with L-gulopyranose. Adenomycin 6,8 a nucleoside an-
tibiotic compound, has a L-gulosamine unit b-linked to chiro-
inositol. Alginate 7,9 which is a non-toxic linear polysac-
charide extracted from seaweed, comprises various propor-
tions of b-D-mannuronic acid and a-L-guluronic acid jointed
by 1®4 linkages. It has shown not only potent antitumor ac-
tivity in vivo9b but also antiviral activity against infection by
tobacco mosaic virus.9c
known as rare sugars from natural sources, are key compo-
nents of numerous biologically potent oligosaccharides, anti-
biotics, glycopeptides, steroid glycosides, as well as terpene
glycosides.1 For example, L-idose and its derivatives form an
important group of vital structural elements of biomolecules.
Heparin, heparan sulfate, and dermatan sulfate, the linear sul-
fated polysaccharides of glycosaminoglycans covalently
bound to a core protein, play significant roles in a diverse set
of biological processes, including blood coagulation, cell
growth control, inflammation, wound healing, virus infec-
tion, tumor metastasis, and diseases of the nervous system.2
Heparin is widely used as an anticoagulant drug in clinics3
and contains a trisulfated disaccharide repeating unit 1 as the
major component consisting of alternating D-glucosamine
and L-iduronic acid with a1®4 linkages. The same unit also
occurs in cell surfaced-heparan sulfate as a minor but essen-
tial constituent, whereas dermatan sulfate is composed of a
D-galactosamine-b1®4-L-iduronic acid disaccharide repeat-
ing unit 2. Neomycin B 3, an aminoglycoside antibiotic pos-
sessing specific interaction with the A site of the prokaryotic
16S rRNA4 and inhibition for the binding of the HIV Rev pro-
tein to its viral RNA recognition site (RRE),5 has 2,6-diami-
no-2,6-dideoxy-L-idopyranose as the D-ring. 6-Deoxy-L-ido-
pyranose is found as a basic component of the diterpene
glycoside 4, isolated from Aster spathulifolius maxim.6
Some remarkable examples are presented by L-gulo-
pyranoside-containing compounds. Bleomycin A2 57 is a sig-
L-Talose 10 and its derivatives are also found in some
natural compounds. Amongst other antibiotics with promis-
ing antibacterial properties, capuramycin 810 contains a 3-O-
methyl-L-talofuranosyl sugar unit, whereas acovenosides11
and maduralide12 have 6-deoxy-3-O-methyl-L-talopyranose
9 (L-acovenose) as the carbohydrate motif.
Other notable examples include L-altrose 11 and L-
mannose 12. The former is a typical constituent of the extra-
cellular polysaccharides from Butyrivibrio fibrisolvens strain
CF3.13 The latter is found in some steroid glycosides,14 and its
phenol derivatives are potent substrates for measuring the
a-L-mannosidase activity of commercial naringinase.15
Since these frequently encountered L-hexoses and 6-
deoxy-L-hexoses are not commercially available, their syn-
thesis has been an area of intense investigation for chemists.16
To tackle this problem, we planned to first achieve the con-
version from D-gluco to L-ido configuration in the shortest
Dedicated to Professor Sunney I. Chan on the occasion of his 67th birthday and his retirement from professional life.

1194 J. Chin. Chem. Soc., Vol. 51, No. 5B, 2004
Kulkarni et al.
Fig. 1. Structures of some biologically potent compounds containing L-hexoses or 6-deoxy-L-hexoses as key components.
possible way and then carry out the specific epimerization of
the L-ido sugars at C2, C3 and/or C4 to get to the whole set of
L-hexoses. Our idea, as illustrated in Scheme I, was to use
double ketal fixation on the 1,2- and 3,5-dihydroxy groups of
D-glucose to form the cis-anti-cis-fused tricyclic D-gluco-
furanose 13, which may undergo elimination to yield the enol
ethers 14 with the requisite 5-exo-double bond. Owing to the
steric congestion on the a-face, stereoselective hydrobora-
tion and hydrogenation of 14 are expected to furnish the de-
sired L-idofuranose 15 and 6-deoxy-L-idofuranose 16, re-
spectively.
RESULTS AND DISCUSSION
Synthesis of L-Idose
Scheme II outlines our efficient synthesis of L-idose. In
the initial attempt,17 3,5-O-benzylidenation (PhCHO, ZnCl2,
32%) of 1,2-O-isopropylidene-a-D-glucofuranose 17 fol-
lowed by sequential Mitsunobu-type iodination (Ph3P, DEAD,
MeI, 75%) and b-elimination (DBU, 92%) furnished the ole-
fin 18 in three steps. As per our expectation, hydroboration of
compound 18 led to the b-L-idofuranosyl sugar 19 (90%) as a
single diastereoisomer in excellent selectivity. Although the
Scheme I
H
H
H
Y
O
H
O
H
O
O
O
O
R3
R4
R3
R4
R3
R4
H
O
O
hydroboration (for 15)
hydrogenation (for 16)
O
R1
R1
elimination
R1
O
O
O
O
O
O
R2
R2
R2
OH
X
14
13 : D-glucofuranose
15 : X = H, Y = OH
16 : X = Y = H

L-Hexoses and 6-Deoxy-L-Hexoses
J. Chin. Chem. Soc., Vol. 51, No. 5B, 2004 1195
Scheme II
HO
1. PhCHO,
HO
OH
O
ZnCl2, 32%
2. Ph3P, DEAD,
MeI, 75%
O
O
O
3. DBU, 92%
H
H
HO
BH3/THF;
H2O2, NaOH
O
H
O
H
HO
17
OH
HO
O
O
0.2 N H2SO4
35 oC, 93%
O
O
O
O
R1
R1
O
O
O
O
O
HO
OH
OH
O
R2
R2
23
Ph3P, NBS;
DBU, 63%
18 : R1 = Ph, R2 = H
21 : R1 = R2 = Me
19 : R1 = Ph, R2 = H, 90%
22 : R1 = R2 = Me, 92%
O
20
strategy works well, there are certain disadvantages of this
route, including (1) it takes four steps to generate the desired
L-ido product 19, (2) tedious purification of each intermedi-
ate is necessary, (3) the overall 22% yield from 17 to 18 is
low, and (4) the starting material 17 is more expensive than
common D-glucose derivatives. To improve these unsatisfac-
tory results, we have developed another convenient and prac-
tical synthesis of L-idose 23 from commercially available and
cheap diacetone a-D-glucose 20 in only three steps.18,19 Con-
secutive treatment of 20 with triphenylphosphine (PPh3),
N-bromosuccinimide (NBS), and DBU provided the enol
ether 21 (63%) in a one-pot manner via a tandem isopropyl-
idene rearrangement, regioslective C6-bromination, and b-
elimination.19 Hydroboration of compound 21 proceeded
well with expected high selectivity, and the corresponding al-
cohol 22 was obtained in 92% yield. Hydrolysis of 22 in 0.2 N
H2SO4(aq) at 35 °C successfully afforded L-idose 23 in excel-
lent yield (93%).
tion, and the 6-deoxy-b-L-idofuranose derivative 24 was ob-
tained as a single diastereoisomer in high yield (87%).18 This
result was exploited to synthesize two important 6-deoxy-L-
hexoses, as depicted in Scheme III.20 Compound 24 upon hy-
drolysis in the presence of an acidic resin provided the ex-
pected 6-deoxy-L-idose, which was directly per-O-acetylated
to its tetraacetate derivatives 25a (33%) and 25b (50%), in
order to circumvent its possible inter-conversion to 6-de-
oxy-L-sorbose. Alternatively, selective hydrolysis of 24 un-
der mild acidic conditions gave the 3,5-diol 26 (81%), which
underwent regioselectively silylation at O5 to furnish the cor-
responding alcohol 27 (TBDMSCl, imidazole, 86%). The
C3-epimerisation was then achieved through an oxidation-
reduction sequence to afford the 6-deoxy-b-L-talofuranosyl
sugar 28 (82% in two steps). 3-O-Methylation of compound
28 (NaH, MeI, 86%) followed by hydrolysis (Amberlite-120
acidic resin, 84%) yielded the desired target molecule L-
acovenose 9.
Synthesis of 6-Deoxy-L-idose and L-Acovenose
Synthesis of L-Talose, L-Altrose, and L-Mannose
For the preparation of other L-hexoses, it was realized
that the free hydroxy group at the C6 position of the L-ido-
As anticipated, the high stereoselectivity observed in
the hydroboration of 21 was also realized in its hydrogena-
Scheme III
H
O
H
1. Amberlite-120
OAc
AcO
AcO
H3C
O
10% Pd/C, H2
87%
acidic resin
Me
Me
OAc
O
O
O
21
+
O
O
2. Ac2O, Pyr.
AcO
OAc
AcO
OAc
24
25a : 33%
25b : 50%
65% AcOH,
40 oC, 81%
Me
Me
Me
HO
OH
OTBDMS
OH
OTBDMS
OH
1. PDC, Ac2O
1. NaH, MeI, 86%
TBDMSCl
imidazole, 86%
O
O
O
9
2. Amberlite-120
acidic resin, 84%
2. NaBH4
O
O
O
O
O
O
82% in two steps
28
26
27

1196 J. Chin. Chem. Soc., Vol. 51, No. 5B, 2004
Kulkarni et al.
furanose 22 makes it an unsuitable precursor due to the diffi-
culties in epimerisation of the remaining chiral centers.
Regioselective hydrolysis of 22 followed by 5,6-O-isopro-
pylidenation furnished the 3-alcohol 29 in 65% overall yield
in two steps. With the appropriate synthon 29 in hand, the
synthesis of various L-hexoses (Scheme IV) was successfully
carried out taking advantage of the 5,5-cis-fused ring config-
uration that allows the nucleophilic and electrophilic addi-
tions only from the b-face.
L-altrofuranosyl sugar 34 (78%) as a single diastereoisomer.
Acidic hydrolysis of the alcohol 34 in the presence of
Amberlite-120 resin led to L-altrose 1121 in excellent yield.
It was envisioned that the L-manno sugars could be ac-
cessed via simultaneous epimerisation of 29 at both C3 and
C4 chiral centers. Enolization of the ketone 30 with acetic an-
hydride in pyridine provided the enol acetate 35 (83%),
which was hydrogenated stereoselectively to provide the
L-mannofuranosyl derivative 36 (74%). Sequential deacet-
ylation (98%) and acidic hydrolysis (100%) of 36 gave the
desired L-mannose 12.21
Since L-talose 10 is a C3-epimer of L-idose 23, we em-
ployed a simple oxidation-reduction protocol for inversion of
compound 29 at C3. Oxidation of 29 with pyridinium dichro-
mate and acetic anhydride led to the ketone 30 (98%), which
was subjected to sodium borohydride reduction to give
1,2:5,6-di-O-isopropylidene-b-L-talofuranose 31 in 92%
yield. Hydrolysis of 31 using Amberlite-120 acidic resin
smoothly afforded L-talose 1019 in quantitative yield. On the
other hand, methylation of 31 allowed us to introduce a
methyl group at O3, and the ether 32 was obtained in 93%
yield. Consecutive removal of the 5,6-O-isopropylidene
group (64% HOAc(aq), 92%) and regioselective 6-O-silyla-
tion (TBDPSCl, cat. DMAP, Et3N, 77%) furnished the corre-
sponding 5-alcohol, which is a key intermediate for the total
synthesis of capuramycin.10b
Synthesis of 1,6-Anhydro-b-L-hexopyranoses
The D- and L-form 1,6-anhydro-b-hexopyranoses are
valuable building blocks in the synthesis of oligosaccharides,
glycoconjugates, as well as natural products.22 A straightfor-
ward synthesis of various rare 1,6-anhydro-b-L-hexopyr-
anosyl sugars is summarized in Scheme V. Reflux of com-
pound 22 in a 0.2 N ethanolic solution of HCl yielded the
1,6-anhydro-b-L-idopyranose 37 (88%) as a single product.23
Subsequently, we developed efficient protocols for regio-
selective protection and selective epimerisation of individual
chiral centers in the triol 37 that paved the way to other rare
1,6-anhydro sugars and consequently to L-hexoses.19,24
Benzoylation of the triol 37 afforded the 2,3-di-OBz 38
(53%) as a major compound. Triflation of the 4-alcohol 38
furnished the corresponding 4-OTf product 39 (90%), which
underwent nucleophilic substitution with NaNO2 in HMPA to
provide the expected 1,6-anhydro-b-L-altropyranosyl sugar
40 (77%). Acetolysis of compound 40 proceeded very well,
and the fully protected L-altrose derivative 4123 was obtained
in 94% yield.
The difference between L-altrose 11 and L-idose 23 is
only at the C4 position. Epimerization of the 3-alcohol 29 to
the corresponding L-altrofuranosyl sugar was thought feasi-
ble via elimination of a water molecule to form a double bond
at C3 and C4 followed by stereoselective hydroboration of
the resulting olefin. Reaction of 29 with diethylaminosulfur
trifluoride (DAST) and pyridine afforded the enol ether 33
(51%), which upon hydroboration yielded the expected
Scheme IV
O
1. 80% HOAc
2. CSA, acetone,
Me2C(OMe)2
O
O
O
O
O
OH
O
Amberlite-120
O
O
PDC, Ac2O
98%
NaBH4
acidic resin
22
10
65% in two steps
MeOH, 92%
100%
O
O
O
O
O
O
RO
O
30
29
NaH, MeI 31 : R = H
11
93%
32 : R = Me
DAST,
Ac2O,
Pyr., 83%
Pyr., 51%
Amberlite-120
acidic resin, 80%
O
O
HO
O
O
BH3/THF
Pd/C, H2
74%
1. NaOMe, 98%
O
O
O
O
12
O
O
O
O
O
O
O
H2O2, NaOH
78%
2. Amberlite-120
acidic resin
100%
O
O
AcO
O
O
OAcO
33
34
35
36

L-Hexoses and 6-Deoxy-L-Hexoses
J. Chin. Chem. Soc., Vol. 51, No. 5B, 2004 1197
Scheme V
HO
TFA,
BzO
OAc
O
O
HO
BzO
TfO
BzO
O
AcO
AcO
Tf2O, Pyr.
90%
NaNO2
77%
Ac2O
O
BzO
BzO
BzO
94%
BzO
40
O
O
O
OBz
41
38
39
BzCl, Pyr., 53%
HO
TFA,
R
BzO
OAc
N3
AcO
O
O
O
Tf2O, Pyr. or
RO
RO
NaNO2
BzO
BzO
Ac2O
0.2 N HCl
O
HO
22
Tf2O, Pyr.; BzCl
88%
89%
or NaN3
HO
TfO
O
O
O
BzO
37
42 : R = H
44 : R = OH, 91%
45 : R = N3, 90%
46
43 : R = Bz, 78%
TMSCl, Et3N
98%
HO
OH
O
TMSO
TMSO
O
O
NaNO2
41% in
TfO
BnO
BnO
TMSO
TfO
50
O
O
O
two steps
51
47
Tf2O, Pyr.
cat. TMSOTf, PhCHO,
Et3SiH, 72%
R
O
O
O
RO
BnO
HO
BzCl, Pyr. or
NaNO2
BnO
BnO
BzCl, Pyr.; Tf2O
or NaN3
BzO
BzO
HO
O
O
O
52 : R = H, 85%
54 : R = OH, 84%
55 : R = N3, 87%
48
53 : R = Tf, 88%
t-BuOK; 0.2 N H2SO4,
diglyme, 160 oC, 52%
Tf2O, Pyr.;
BzCl, 94%
R
BzO
O
BzO
BnO
O
NaNO2
BzO
BnO
OBn
O
MsO
or NaN3
TfO
O
O
O
57 : R = OH, 91%
58 : R = N3, 97%
56
O
49
Reaction of compound 37 with one equiv of trifluoro-
methanesulfonic anhydride in pyridine led to the 2-OTf com-
pound 42 as a single isomer in excellent selectivity. One-pot
triflation-benzoylation of 37 successfully yielded the corre-
sponding ester 43 (78%), which was treated with NaNO2 or
NaN3 to give the 1,6-anhydro-b-L-gulopyranose 44 and its
2-azido derivative 45. Conversion of 45 into the ring opened
adduct 46 (89%) was similarly carried out under acetolysis
conditions. It is believed that the fully protected L-gulos-
amine derivative 4623 could be a potential precursor in the
synthesis of adenomycin 6.8
compound 49 with t-BuOK in t-BuOH followed by heating in
a 1:2 mixture of 0.2 N H2SO4(aq) and diglyme at elevated tem-
perature (160 °C) led to 48 in a moderate 52% yield in a one-
pot manner.26 Similarly, consecutive triflation and nucleo-
philic substitution of the diol 48 via the 2,4-di-OTf 50 as an
intermediate furnished the corresponding L-allo 2,4-diol 51
in 41% overall yield in two steps.
In comparison with compound 37, the regioselectivity
observed in the benzoylation and/or triflation of the diol 48 is
extremely high wherein the O3 position is fixed with a benzyl
group. Selective benzoylation of 48 with BzCl in pyridine at
0 °C led to the 2-OBz 52 (85%) as a single isomer. One-pot
benzoylation-triflation of 48 provided the 2-OBz-4-OTf de-
rivative 53 (88%), which was subjected to SN2 substitutions
with NaNO2 and NaN3 to afford the 1,6-anhydro-b-L-altro-
pyranosyl sugar 54 (84%) and its 4-azido derivative 55
On the other hand, regioselective 3-O-benzylation of
the potent synthon 37 employing TMSOTf-catalyzed Et3SiH-
reductive etherification of its O-trimethylsilylated ether 47
(98%) gave the corresponding 3-OBn 48 (72%) in very good
selectivity.24,25 Alternatively, treatment of the 5-OMs-6-OBz

1198 J. Chin. Chem. Soc., Vol. 51, No. 5B, 2004
Kulkarni et al.
(97%), respectively. A mere reversal in the order of reagent
addition to the diol 48 (Tf2O, then BzCl) resulted in the for-
mation of the 2-OTf-4-OBz compound 56 (95%). Similar
substitutions were applied to synthesize the 1,6-anhydro-b-
L-gulopyranosyl sugars 57 and its 2-azido derivative 58 in
91% and 97% yields, respectively.
the total synthesis of bleomycin A2.7
Synthesis of Heparin Oligosaccharides
The application of the versatile synthon 52 in the syn-
thesis of heparin oligosaccharides 85-88 is illustrated in
Scheme VII.26 The 1,3-diol 66, derived from D-glucosamine
via a two-stepped combination of amino-azido conversion
and 4,6-O-naphthylidenation, underwent consecutive O1-
benzoylation29 and O3-benzylation to afford the fully pro-
tected compound 67 (67% from 66). A highly regioselective
borane-reductive ring opening of the 4,6-O-benzylidene
acetals to the corresponding 4-OBn-6-OH derivatives em-
ploying VO(OTf)2 as the catalyst was recently developed by
us.30 Reaction of 67 under the same conditions provided the
desired 6-alcohol (84%), which was subjected to O6-benzo-
ylation (90%) followed by O1-debenzoylation (96%) to fur-
nish the 1-alcohol 68. Transformation of 68 into the corre-
sponding trichloroacetimidate and further coupling with 52
led to the expected a-linked disaccharide 69 in 61% yield.
Cu(OTf)2-catalyzed acetolysis of 69 with acetic anhydride
gave the 1,6-diacetate 70 (88%) which, upon O1-deacetyla-
tion and imidation yielded the desired glycosyl donor 71
(77%). The 4-alcohol 72, prepared from the known methyl
2-azido-3-O-benzyl-2-deoxy-a-D-glucopyranoside by selec-
tive benzoylation at O6,31 was coupled with 71 to get the
a-linked trisaccharide 73 (89%) as a single isomer. Further
chain-elongation sequence, involving selective removal of
the O4-NAP using DDQ and subsequent glycosylation with
the disaccharide donor 71, was successfully carried out, and
the pentasaccharide 74 was obtained in 58% yield. While re-
Synthesis of the Carbohydrate Moiety of Bleomycin A2
The construction of the disaccharide subunit in bleo-
mycin A2 requires the assembly of 3-O-carbamoyl-D-manno-
pyranosyl donor and L-gulopyranosyl acceptor with a a1®2
linkage. Scheme VI describes our concise synthesis of this
carbohydrate moiety using the 1,6-anhydro-b-L-gulopyr-
anosyl alcohol 44 as a key synthon.19 Commercially available
1,6-anhydro-b-D-mannopyranose 59 was treated with benzo-
yloxybenzotriazole (BzOBT) to yield the expected 2,4-di-
OBz adduct 60 (54%) as a major isomer, which was con-
verted into the corresponding 3-carbonate 61 (89%). Cu(OTf)2,
a cheap, water-stable, and reusable catalyst, can be used for a
variety of transformations.27 Cu(OTf)2-catalyzed acetolysis28
of compound 61 with Ac2O followed by addition of 30% HBr
in acetic acid gave the glycosyl bromide 62 (90%) in a one-
pot manner. Hydrolysis of this crude compound 62 with
AgOTf in water provided the 1-alcohol (93%) which, upon
sequential imidation (K2CO3, CCl3CN, 89%) and coupling
with 44 furnished the a-linked disaccharide 63 in 82% yield,
exclusively. Acetolysis of 63 in the presence of Cu(OTf)2 as
the catalyst afforded the expected diacetate 64 (74%), which
underwent one-pot nucleophilic displacement with ammonia
to get the desired product 65 (77%), a suitable precursor for
Scheme VI
N
O
Br
N
O
OAc
OBz
cat. Cu(OTf)2, Ac2O;
30% HBr in AcOH
PNPO
O
HO
HO
N
O
HO
BzO
O
O
O
O
PNPO
Bz
Cl
BzO
O
OPNP
O
O
O
BzO
Pyr., 54%
DMAP, Pyr.
89%
90%
OBz
OH
OBz
O
61
59
60
62
OBz
1. AgOTf, 93%
2. CCl3CN, K2CO3
89%
O
OH
O
OAc
BzO
BzO
AcO
NH3
AcO
Cu(OTf)2,
Ac2O
OBz
O
O
O
O
O
OAc
OBz
NH2
OAc
O
OAc
OBz
OPNP
BzO
O
BzO
74%
OBz
77%
3. TMSOTf, 44
O
82%
OPNP
O
O
BzO
BzO
O
BzO
O
O
O
65
64
63

L-Hexoses and 6-Deoxy-L-Hexoses
J. Chin. Chem. Soc., Vol. 51, No. 5B, 2004 1199
Scheme VII
1. cat. VO(OTf)2
1. CCl3CN,
OBz
2-Naph
2-Naph
BnO
BH3/THF, 84%
1. BzOBT, Et3N
O
O
K2CO3, 98%
O
O
O
2-NAPO
BnO
O
O
OH
OBz
OH
HO
2. BzCl, Pyr., 90%
3. NH3(g), 96%
2. Ag2O, BnBr
67% in 2 steps
2. cat. TMSOTf, 52
N3
66
N3
67
N3
68
61%
NH
OBz
OBz
OR
OCCCl3
BnO
BnO
O
O
HO
BnO
RO
RO
O
2-NAPO
BnO
O
cat.Cu(OTf)2,
Ac2O
N3
1. NH3(g)
OMe
72
N3
O
OBz
O
OBz
O
O
BnO
OBz
O-2-NAP
OBn
OBz
O-2-NAP
88%
2. CCl3CN,
DBU
cat. TMSOTf
O
O
N3
N3
BzO
O
OBn
69
1. PTSA, 81%
70 : R = Ac
75 : R = Lev
71 : R = Ac, 77%
76 : R = Lev, 53%
2. (Lev)2O, Pyr., 97%
OMe
O
OMe
N3
OMe
N3
N3
BnO
BnO
HO
O
O
O
O
OBz
O
OSO3
-
OBz
1. NaOMe
BnO
BnO
O
HO
RO
2. SO3/Et3N
1. H2NNH2/AcOH
2. TEMPO, NaOCl
O
HO2C
O
HO2C
O
-
3. Pd/C, H2
4. SO3/Pyr.,
pH = 9.5
O
OBz
OBz
O
OSO3
-
OBz
OBz
O
OSO3
O
O
O
-O3SHN
N3
N3
O
O
OBn
OBn
OH
n
n
n
2-NAP
2-NAP
H
85 : 36%
86 : 21%
87 : 8%
88 : 6%
81 : n = 1, 84%
82 : n = 2, 71%
83 : n = 3, 69%
84 : n = 4, 62%
73 : R = Ac, n = 1, 89%
74 : R = Ac, n = 2, 58%
77 : R = Lev, n = 1, 84%
78 : R = Lev, n = 2, 59%
79 : R = Lev, n = 3, 57%
80 : R = Lev, n = 4, 49%
1. DDQ; 2. 71, TMSOTf
1. DDQ; 2. 76, TMSOTf
1. DDQ; 2. 76, TMSOTf
1. DDQ; 2. 76, TMSOTf
action of compound 73 with HBF4·Et2O afforded the corre-
sponding 6¢-alcohol in excellent yield, simultaneous removal
of two acetyl groups in 74 did not provide us the expected
6,6¢-diol.
fates, obtained by consecutive deacetylaion and O-sulfona-
tion of 81-84, underwent hydrogenolysis to reduce the OBn,
O-2-NAP, and N3 groups simultaneously and subsequent
N-sulfonation to give the target molecules 85-88, respec-
tively.
At this stage, we switched the acetyl groups to levu-
linoyl (Lev) esters. Thus, deacetylation of compound 70 fur-
nished the 1,6-diol (81%), which was reacted with Lev2O in
pyridine to yield the ester 75 (97%). A similar reaction se-
quence of anomeric deprotection and imidate formation led
to the glycosyl donor 76 (53% in 2 steps), which was coupled
with 72 in a likewise manner to construct the a-linked tri-
saccharide 77 (84%). The elongation cycle was then repeated
thrice to assemble the penta-, hepta- and nonasaccharides 78,
79, and 80, respectively. Cleavage of the Lev groups in 77-80
followed by TEMPO oxidation, individually, furnished the
acids 81-84 in good overall yields. The corresponding O-sul-
CONCLUSIONS
We have successfully developed a straightforward
route to prepare the biologically important and rare L-hex-
oses and 6-deoxy-L-hexoses from the most abundant D-glu-
cose via their corresponding furanosyl and 1,6-anhydropyr-
anosyl derivatives as key intermediates. The method, being
amenable to scale-up operation, is expected to find a wide use
and provide a steady supply of rare sugars to those in its con-

1200 J. Chin. Chem. Soc., Vol. 51, No. 5B, 2004
Kulkarni et al.
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have uncovered some interesting facets and reactivity pat-
terns exhibited by these conformationally biased synthons.
Applications of these new developments to the syntheses of
heparin oligosaccharides, the disaccharide moiety of bleo-
mycin A2, and L-acovenose have been demonstrated.
ACKNOWLEDGEMENTS
We thank our group members, whose names are cited in
the references, for their intellectual and experimental contri-
butions. Scientific discussions with Profs. Chun-Chen Liao
and Biing-Jiun Uang are gratefully acknowledged. This work
was supported by the National Science Council of Taiwan
(NSC 91-2113-M-001-004 and NSC 91-2323-B-001-006).
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Received March 23, 2004.
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